Developmentally regulated histone modification and DNA methylation changes, shaping gene expression patterns and genome organization, are likely to be of fundamental importance for orderly ontogenesis and cellular differentiation. Therefore, comprehensive and high resolution mapping of cell type-specific epigenomes from brain bear enormous merit both from the viewpoint of developmental biology and translational medicine alike. To date, however, comprehensive and genome-wide maps of epigenomes for defined cell populations from brain, and their developmental trajectories, do not exist. This important gap in epigenetic information can finally be addressed with a recently introduced protocol that efficiently separates-in brain tissue-chromatin from different cell types. In this proposal, we will explore, for the first time, the histone methylation landscapes of ventral midbrain dopaminergic neurons of the human brain. These cells play a key role in the neurobiology of a wide range of neuropsychiatric disorders ranging from drug addiction to neurodegenerative (e.g., Parkinson's) conditions. Focus will be on tri-methyl-histone H3-lysine 4 (H3K4me3), a mark enriched at transcription start sites (H3K4me3) and a subset of CpG-rich sequences, and tri-methyl-H3K36me3, a mark associated with RNA polymerase II activity and transcriptional elongation across coding and non-coding regions. Beyond the goals of this R21 proposal, the long-term vision for the collaboration between our two groups at Wayne State and UMASS is to explore changes in the dopaminergic epigenome of subjects diagnosed with stimulant and other substance abuse.